Tauroursodeoxycholic acid: a potential therapeutic tool in neurodegenerative diseases

Abstract

Most neurodegenerative disorders are diseases of protein homeostasis, with misfolded aggregates accumulating. The neurodegenerative process is mediated by numerous metabolic pathways, most of which lead to apoptosis. In recent years, hydrophilic bile acids, particularly tauroursodeoxycholic acid (TUDCA), have shown important anti-apoptotic and neuroprotective activities, with numerous experimental and clinical evidence suggesting their possible therapeutic use as disease-modifiers in neurodegenerative diseases. Experimental evidence on the mechanisms underlying TUDCA’s neuroprotective action derives from animal models of Alzheimer’s disease, Parkinson’s disease, Huntington’s diseases, amyotrophic lateral sclerosis (ALS) and cerebral ischemia. Preclinical studies indicate that TUDCA exerts its effects not only by regulating and inhibiting the apoptotic cascade, but also by reducing oxidative stress, protecting the mitochondria, producing an anti-neuroinflammatory action, and acting as a chemical chaperone to maintain the stability and correct folding of proteins. Furthermore, data from phase II clinical trials have shown TUDCA to be safe and a potential disease-modifier in ALS. ALS is the first neurodegenerative disease being treated with hydrophilic bile acids. While further clinical evidence is being accumulated for the other diseases, TUDCA stands as a promising treatment for neurodegenerative diseases.

Tauroursodeoxycholic acid in patients with amyotrophic lateral sclerosis: The TUDCA-ALS trial protocol

“…This corresponds to a prolongation of median survival by 4-5 months. This indication of efficacy is further supported by the evidence that TUDCA has cytoprotective properties in animal models of different neurodegenerative diseases (5). Recently, another phase II trial on TUDCA Abbreviations: ALS, amyotrophic lateral sclerosis; ALSAQ , ALS Assessment Questionnaire-; ALSFRS-R, ALS functional rating scalerevised; CRO, contract research organization; CSF, cerebrospinal fluid; eCRF, electronic case report form; EQ-D-L, EuroQol -Dimension-L; FVC, forced vital capacity; GCP, good clinical practice; IMP, investigational medicinal product; IIH, Italian Institute of Health; ITT, intention to treat; MMP-, matrix metalloproteinase-; MRC, Medical Research Council; NFL, neurofilament light chain; pNFH, neurofilament heavy chain; SOPs, standard operating procedures; TUDCA, tauroursodeoxycholic acid; UDCA, ursodeoxycholic acid.…”

“…This corresponds to a prolongation of median survival by 4–5 months. This indication of efficacy is further supported by the evidence that TUDCA has cytoprotective properties in animal models of different neurodegenerative diseases ( 5 ). Recently, another phase II trial on TUDCA combined with sodium phenylbutyrate showed a positive effect on disease progression, further supporting a possible role of TUDCA in reducing ALS progression ( 9 ).…”

“…It has been shown that TUDCA has neuroprotective effects in motor neuronneuroblastoma hybrid cells expressing mutant superoxide dismutase 1 mutations A4V and G93A (13). Preclinical data also report an anti-apoptotic and neuroprotective role of TUDCA in models of different neurodegenerative diseases (5).…”

“…In ALS, disease progression is rapid and can be measured by survival or functional measures, but detecting clinically significant change still requires long treatment duration and large study populations ( 4 ). The pathogenic mechanisms proposed for ALS involve a plethora of alterations to the motor neuron microenvironment, including accumulation of protein aggregates, defective RNA processing, oxidative stress, glutamate excitotoxicity, axonal transport deficits, glial dysfunction, neuroinflammation, apoptosis, mitochondrial dysfunction, fragmentation of the Golgi apparatus, and metal imbalances ( 5 ). Although much has been achieved over the last two decades in understanding the disease complexity, currently there is no cure for ALS.…”

“…It is commonly used for the treatment of chronic cholestatic liver diseases and for gallstone ( 10 ). TUDCA is the active natural form of UDCA; it is orally bioavailable and blood–brain barrier permeable ( 5 , 11 ). After oral administration, TUDCA is absorbed at the bowel level.…”